What are the risk factors for recurrence?
HCC recurrence is generally believed to have two origins. One is the single-center origin in which intrahepatic micro-metastases of the primary tumor or microthrombi before or after hepatectomy. This kind of recurrence usually occurs within 2 years after initial curative treatment, and is termed an early recurrence. The other is the multicenter origin, which occurs late, usually more than 2 years after surgery. Patients with late recurrence have a significantly better prognosis than those with early recurrence, which means that different types of recurrence have different risk factors.18,19 Many studies indicated the main risk factors of early-phase recurrence include tumor size more than 5 cm, multiple tumors, satellites, absence of a tumor capsule, tumor rupture, non-anatomical resection, narrow resection margin (≤2 cm), alpha-fetoprotein ≥400 ng/mL, as well as micro- and macrovascular invasion. In randomized trials, high-risk features for hepatectomy patients included tumor size >5 cm, more than three tumors, microvascular invasion (MVI), macrovascular invasion, and poor tumor differentiation.11–16 Risk factors of late-phase recurrence included liver cirrhosis, higher grade of hepatitis activity, and poor tumor classification.20–22 HCC patients usually have underlying chronic liver disease or cirrhosis caused by chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, alcoholic, or nonalcoholic steatohepatitis.23 They thus always have early and late phase recurrence risk factors.
The existence of high-risk recurrence factors means that the probability of residual tumor in the remanent liver is higher and the possibility of early recurrence is greater, which seriously affects the overall effectiveness of surgical treatment and patient quality of life. Adjuvant therapy after local treatment of HCC aims to reduce the recurrence rate and thus increase RFS and OS. In fact, local (hepatectomy or ablation) and adjuvant treatment can be complementary. On one hand, local treatment reduces tumor burden and induces the release of tumor antigens and pro-inflammatory cytokines. On the other hand, adjuvant immunotherapy and tyrosine kinase inhibitors can boost antitumor immunity. The different risk factors for the two types of recurrence suggest that different targets should be targeted when designing adjuvant therapy. For intrahepatic metastasis, the primary strategy should target disseminated tumor cells that have spread from the primary tumor, just as in transarterial chemoembolization (TACE). For de novo carcinogenesis, the strategy is to control the progression of hepatitis or cirrhosis, as in antiviral treatment.24 The effective elimination of residual tumors or prevention of intrahepatic metastasis with adjuvant therapy can help reduce early recurrence, which may be a reason that adjuvant therapy is more suitable for patients with high-risk factors of recurrence. However, few studies have shown that postoperative antiproliferative and anti-angiogenic therapy reduce latent intrahepatic and extrahepatic spread, which is often associated with the risk of early recurrence.
What are the strategies for adjuvant therapy?
Antiviral therapy
There are multiple goals for antiviral therapy in patients with hepatitis-related HCC. On the basis of comprehensive treatment of HCC, antiviral therapy maximizes long-term inhibition of virus replication, reduces liver damage caused by the virus, prevents disease progression, provides a good basis for liver function, reduces the risk of postoperative recurrence, and ultimately prolongs patient survival.25,26 In HCV-related HCC, sustained viral eradication obtained by interferon-based or interferon-free regimens significantly reduces tumor recurrence without differences associated with the antiviral strategy used.27 However, a meta-analysis showed that recurrence risk and survival were extremely variable in patients with successfully treated HCV-related HCC, providing a useful benchmark for indirect comparison of the benefits of direct-acting antivirals.28 In addition, a high HBV load has been associated with poor RFS and OS in patients with HCC after hepatectomy.21,29 Therefore, antiviral therapy is crucial for preventing postoperative recurrence of HBV- or HCV-related HCC.
Nucleos(t)ide analogs
Several randomized trials reported the positive efficacy of postoperative treatment with nucleos(t)ide analogs for HBV-related HCC, with reduced viral load, decreased tumor recurrence, and improved OS. A meta-analysis of 21 studies including 8,752 patients explored the efficacy of nucleos(t)ide analogs for patients with HBV-related HCC after curative hepatectomy. It found that postoperative nucleos(t)ide analog therapy significantly reduced early recurrence rate and improved OS.30 The use of nucleos(t)ide analogs for postoperative HBV-related HCC is recommended by several HCC treatment guidelines.2,17,31
Nucleos(t)ide analogs include lamivudine, adefovir dipivoxil, entecavir, tenofovir, and others. Previous study found adefovir dipivoxil and lamivudine were associated with similar survival benefits in patients with HBV-related HCC after curative hepatectomy, and that adefovir dipivoxil was more cost-effective.32 Tenofovir has been associated with significantly lower HCC risk than entecavir in patients with chronic HBV infection who are from Asia and/or nucleos(t)ide naïve.33,34 A recent randomized trial including patients with HBV-related HCC after curative hepatectomy, reported that consistent tenofovir therapy was associated with a significantly lower risk of tumor recurrence than entecavir therapy.35 Moreover, when compared with entecavir, tenofovir decreased serum lipoprotein levels in patients with HBV-related HCC.36 Antiviral therapy with tenofovir may thus be the preferred drug for HBV-related HCC after curative treatment.37
Interferon
Many studies reported the safety and efficacy of interferon in the prevention of recurrence after curative hepatectomy for HCC, but with different conclusions. Interferon has various functions such as antiviral replication, antitumor angiogenesis, regulating cell proliferation, immune regulation, and blocking proto-oncogenes. Eight randomized trials reported the safety and efficacy of interferon in preventing postoperative HCC recurrence, of which three enrolled only patients with HCV-related HCC,38–40 one enrolled only HBV-related HCC,41 and the other four included patients with either HBV- or HCV-related HCC.42–45 The reasons for these differences may be heterogeneity of the underlying liver disease and liver reserve function, as well as interferon type, dose, and duration of treatment. A meta-analysis of these eight RCTs concluded that interferon reduced the 2-year recurrence rate and improved the 2-year OS after curative hepatectomy.46 However, another meta-analysis showed that adjuvant interferon was effective in prolonging RFS and OS of HCV-related HCC but not HBV-related HCC, showing that the effectiveness of interferon was different in different populations and viral-related HCC.47 Although adjuvant interferon therapy may be effective, it is associated with many adverse reactions, including fatigue, chills, fever, headache, muscle pain, leukopenia, and thrombocytopenia. Other less common adverse reactions include transaminase elevation and alopecia.
TACE or hepatic arterial infusion chemotherapy
TACE is a key treatment of intermediate-stage HCC. The main purpose of adjuvant TACE is to eradicate tumor cells that may have been released during the intraoperative extrusion and to destroy preexisting microscopic cancer foci that preoperative imaging failed to detect. Randomized trials and retrospective studies with large sample sizes have confirmed that adjuvant TACE reduced the intrahepatic recurrence rate and improved RFS and/or OS after resection.11,12,48 None of these trials included patients who underwent local ablation. A meta-analysis had shown a survival benefit with adjuvant TACE.49 Another meta-analysis including 11,165 patients showed that adjuvant TACE significantly improved RFS and OS compared with curative resection alone. A subgroup analysis showed that adjuvant TACE was more effective in patients with tumor maximum diameters of >5 cm, MVI, and multiple tumors, but had the opposite effects in early HCC patients without MVI, and even decreased RFS.50 The most frequent adverse events of TACE include fever, nausea, ascites, fatigue, leukopenia, and liver function damage. Most patients tolerate it without requiring need symptomatic treatment. All these randomized trials were from China or Japan. The HCC guidelines in Western countries do not recommend adjuvant TACE for HCC.17,51
Hepatic arterial infusion chemotherapy (HAIC) is administered by continuous infusion of chemotherapy drugs into tumor blood vessels with microcatheters. HAIC has the advantages of higher local drug concentration and fewer systemic side effects than systemic chemotherapy. HAIC alone or in combination with immunotherapy or molecular targeted therapy has shown surprising effects in advanced HCC.52–54 A randomized trial enrolled 315 HCC patients with MVI who underwent hepatectomy followed by adjuvant HAIC or routine follow-up. Adjuvant HAIC with FOLFOX significantly improved RFS with acceptable toxicity in HCC patients with MVI.55 However, these findings need to be confirmed by further trials.
During the implementation of TACE and HAIC, digital subtraction angiography (DSA) is required before the drug is injected. DSA can detect residual lesions and determine whether hepatectomy was curative or not. In cases with residual lesions, the purpose of TACE or HAIC is to control residual lesions (so-called recurrence foci). These treatments are not adjuvant therapy. Owing to the absence of DSA detection in the active surveillance group, residual lesions were not found in time. Those who did not achieve genuine curative treatment did not receive TACE or HAIC therapy for residual lesions, and their short-term recurrence rate was significantly higher than that in the treatment group. Although some randomized trials included curative cases, they did not report the specific criteria of “curative”. In addition, those randomized trials did not exclude some cases enrolled after DSA, such as those with residual lesions during imaging. Therefore, the conclusion that adjuvant TACE or HAIC significantly reduced the recurrence rate after curative hepatic resection may not be accurate. If real curative cases were included, positive results might not have been observed. We look forward to RCTs that include genuine curative cases to explore this issue.
Molecular targeted drugs
Whether sorafenib should be used as adjuvant therapy for HCC after curative resection remains controversial. The STORM study explored the safety and efficacy of adjuvant sorafenib treatment of HCC following resection or ablation. The study noted no difference in median RFS in the sorafenib (33.3 months) and placebo groups (33.7 months). Moreover, sorafenib increased the rate of grade 3 or 4 adverse events.13 It is noted that the STORM trial only enrolled a few proportions of patients with a high risk of recurrence. Randomized trials exploring the safety and efficacy of other tyrosine kinase inhibitors (e.g., lenvatinib, apatinib, or donafinib) as adjuvant therapy for HCC after curative hepatectomy are ongoing.
Immunotherapy
Immunotherapy is a therapeutic method of killing tumor cells by stimulating or regulating immune function. Currently, immunotherapy for HCC mainly includes adoptive immunotherapy, immune checkpoint inhibitors (ICIs), tumor vaccines, and others. Several randomized trials have confirmed the safety and efficacy of adjuvant adoptive immunotherapy for patients with HCC after hepatectomy.56–59 These findings were confirmed by meta-analyses.60,61
ICIs are an emerging treatment with great potential for effective treatment of HCC. The success of the IMbrave150 study has laid a solid foundation for the combined use of ICI therapy for advanced HCC.62 A phase II trial with a single arm (n=55) including patients with intermediate or high risk of recurrence who received adjuvant nivolumab had a median RFS of 26 months, but most patients had single tumors with a median diameter of approximately 2.6 cm and no vascular invasion.63 A prospective cohort study included 432 patients receiving no adjuvant therapy (83.6%), 53 (10.2%) who received ICIs alone, and 32 (6.2%) who received adjuvant ICIs plus tyrosine kinase inhibitors. During a median follow-up of 34.0 months, propensity score matching found that RFS and OS were significantly higher in patients who received either type of adjuvant therapy than in those who received no adjuvant therapy. More interestingly, the study found no significant differences in RFS or OS between patients treated with ICIs alone or ICIs with tyrosine kinase inhibitors. The overall study findings imply that ICIs alone or combined with tyrosine kinase inhibitors improved RFS in patients at high risk of HCC recurrence after curative hepatectomy.64 Recently, an interim analysis of IMbrave050 (n=668) reported that at a median follow-up of 17.4 months, adjuvant atezolizumab plus bevacizumab were associated with a significantly lower RFS rate than active surveillance in patients with HCC and a high risk of recurrence (p=0.012). However, the median RFS of both groups had not been reached.65 Longer follow-up is needed to confirm the efficacy of adjuvant atezolizumab plus bevacizumab. Other randomized trials are currently underway, including CheckMate 9DX,14 KEYNOTE-937,15 and EMERALD-216 (Table 1). We are looking forward to the reporting of the trial results.
Table 1Ongoing phase III clinical trials of adjuvant immune checkpoint inhibitors after hepatectomy or ablation
| Trials | ClinicalTrials.gov ID | Sample (n) | Tumor status | Treatment arms | Primary endpoint |
|---|
| CheckMate 9DX | NCT03383458 | 545 | High-risk recurrence | Nivolumab vs. placebo | RFS |
| EMERALD-2 | NCT03847428 | 908 | High-risk recurrence | Durvalumab + bevacizumab vs. durvalumab vs. placebo | RFS |
| IMbrave 050 | NCT04102098 | 668 | High-risk recurrence | Atezolizumab + bevacizumab vs. active surveillance | RFS* |
| KEYNOTE-937 | NCT03867084 | 950 | BCLC 0 or A | Pembrolizumab vs. placebo | RFS, OS |
| JUPITER 04 | NCT03859128 | 402 | High-risk recurrence | Toripalimab vs. placebo | RFS |
| SHR-1210-III-325 | NCT04639180 | 687 | High-risk recurrence | Camrelizumab + apatinib vs. active surveillance | RFS |
Systemic chemotherapy
Theoretically, systemic chemotherapy can control tumor growth and reduce recurrence by killing tumor cells in the blood circulation. However, randomized trials did not find carmofur or uracil tegafur significantly improved RFS or OS.66–68 A small randomized trial (n=60) found that postoperative adjuvant capecitabine therapy significantly reduced the risk of tumor recurrence in HCC patients after hepatectomy, but did not improve OS.69 However, a meta-analysis found no significant benefit of adjuvant oral systemic chemotherapy on OS and RFS.70 Moreover, the adverse events of systemic chemotherapy included transaminase elevation, nausea, diarrhea, and bone marrow suppression.
Radiation therapy
Radiotherapy has gradually become one of the main treatment methods for unresectable HCC.71,72 However, the efficacy of adjuvant radiotherapy for HCC after curative hepatectomy remains controversial. A randomized trial (n=119) found that adjuvant radiotherapy was technically feasible and relatively safe for centrally located HCCs after narrow-margin hepatectomy but did not improve RFS and OS.73 A phase II trial included 76 HCC patients who underwent narrow-margin hepatectomy and then received postoperative intensity-modulated radiotherapy. During a median follow-up of 70 months, the 5-year OS and RFS rates were 72.2% and 51.6%, respectively. No marginal recurrence was found. The most common radiation-associated grade-3 toxicity was leukopenia (7.9%).74 A systematic review including 10 studies (three randomized trials, one phase II trial, and six retrospective comparative studies) found adjuvant external beam radiotherapy significantly improved RFS and OS compared with hepatectomy alone.75 Therefore, the current limited evidence showed that adjuvant radiotherapy was a safe and effective measure to prevent HCC recurrence.
A small randomized trial (n=43) found adjuvant intra-arterial iodine-131 labeled significantly improved RFS and OS in patients with HCC after curative hepatectomy.76,77 However, a larger randomized trial (n=103) did not find a clinical benefit of adjuvant iodine-131 for such patients.78 Therefore, the efficacy of adjuvant iodine-131 in HCC needs to be confirmed by more randomized trials with large samples.
Vitamin K2 analogs
Vitamin K2 analogs (VK2) have been shown to induce cell cycle arrest at the G1/S phase leading to growth inhibition of HCC cells and to have potent anti-angiogenic activity, preventing late recurrence.79 Five randomized trials and one cohort study from Japan reported the controversial efficacy of adjuvant oral VK2 in preventing HCC recurrence and improving survival after curative hepatectomy or ablation.80–85 A meta-analysis of. those studies found that adjuvant VK2 analogs reduced short-term tumor recurrence and improved short-term OS.86 It is noted that the included populations were from Japan. The role of VK2 analogs in other countries or regions remains to be explored.
Traditional Chinese medicine
Chen et al.87 performed a multicenter randomized trial of the efficacy of adjuvant Huaier on long-term prognosis after curative hepatectomy. A total of 1,044 patients with HCC after hepatectomy were randomly assigned to receive Huaier or placebo in a 2:1 ratio. RFS was significantly prolonged and extrahepatic recurrence was reduced in the treatment group. The molecular mechanism of Huaier needs further exploration.
Different recommendations for adjuvant therapy in different countries
Although many randomized trials have explored the efficacy of adjuvant therapy, the findings are different, or the same treatment can lead to inconsistent or even opposite findings. Therefore, recommendations for adjuvant therapy differ greatly in the HCC treatment guidelines in different countries (Table 2). There is an East-West consensus regarding the use of nucleos(t)ide analogs for postoperative treatment of patients with HBV-related HCC. The Chinese guidelines recommend adjuvant TACE and Huaier for HCC patients with a high risk of recurrence (Level 1, Strong Recommendation).2 In contrast, the recommendations of HCC guidelines in other countries are conservative. The Korean HCC guidelines recommend adjuvant adoptive immunotherapy after curative hepatectomy88 and the Japanese guidelines only recommend antiviral therapy for patients with viral hepatitis.3 The National Comprehensive Cancer Network guidelines state that no adjuvant therapies have been shown to have benefits but there are ongoing clinical trials.89 The American Association for the Study of Liver Diseases recommends the use of adjuvant ICI-based systemic therapy in patients at a high risk of recurrence after hepatectomy or local ablation (Level 2, Strong Recommendation).17 However, the European Association for the Study of the Liver and the European Society for Medical Oncology do not recommend any adjuvant therapy for HCC.51,90 As medicine evolves and clinical trials are successful, the gaps in the guidelines for adjuvant therapy will be filled.
Table 2Recommendation of adjuvant therapy for hepatocellular carcinoma in various countries or regions
| Treatment option | EASL 2018 | ESMO 2018 | AASLD 2023 | NCCN 2023 | CNLC 2022 | JSH 2021 | KLCA 2022 |
|---|
| Nucleoside analogs | Routinely used for hepatitis B virus related hepatocellular carcinoma |
|---|
| Interferon | Not recommended | Not recommended | Not recommended | Not recommended | Level 1, Moderate recommendation | Not recommended | Not recommended |
| TACE | Not recommended | Not recommended | Not recommended | Not recommended | Level 1, Strong recommendation | Not recommended | Not recommended |
| HAIC | Not recommended | Not recommended | Not recommended | Not recommended | Exploring | Not recommended | Not recommended |
| TKIs | Not recommended | Not recommended | Not recommended | Not recommended | Exploring | Not recommended | Not recommended |
| ICIs | Clinical trials | Not recommended | Level 2, Strong recommendation | Clinical trials | Exploring | Not recommended | Not recommended |
| Adoptive immunotherapy | Not recommended | Not recommended | Not recommended | Not recommended | Not described | Not recommended | CIK cell (Level 2, Strong recommendation) |
| Systemic chemotherapy | Not recommended | Not recommended | Not recommended | Not recommended | Not described | Not recommended | Not recommended |
| Radiation therapy | Not recommended | Not recommended | Not recommended | Not recommended | Level 2, Moderate/Weak recommendation | Not recommended | Not recommended |
| Vitamin analogs and retinoids | Not recommended | Not recommended | Not recommended | Not recommended | Not described | Not recommended | Not recommended |
| Heparanase inhibitors | Not recommended | Not recommended | Not recommended | Not recommended | Not described | Not recommended | Not recommended |
| Huaier | Not described | Not described | Not described | Not described | Level 1, Strong recommendation | Not described | Not described |
There are many reasons why the recommendations of HCC guidelines in different countries or regions may vary greatly. The first is the difference in treatment philosophy. The treatment model recommended by Chinese HCC guidelines presents a multi-treatment model in which one treatment method can be applied to multiple tumor stages. For example, hepatic resection can be applied to stages Ia to IIIa HCC. Tumors of the same stage can receive a variety of treatments. For example, patients with intermediate or advanced HCC can receive transarterial treatment combined with targeting and immunotherapy. In Western guidelines, a combination treatment model is rarely recommended. Second, Western guidelines attach great importance to quality control at the level of evidence. Only high-level evidence-based treatment would be cited in Western guidelines. Finally, most official HCC guidelines, but not those in China, detail each author’s conflict of interest.